DESCRIPTION: (provided by the applicant) There are few simple, rapid, reliable behavioral assays in rats that are sensitive to cocaine withdrawal symptoms. The purpose of the CEBRA grant is to develop, validate, and characterize such an assay. Considering that drug withdrawal likely contributes to drug-taking in humans, an assay sensitive to cocaine withdrawal may lead to an increased understanding of the neurobiological mechanisms of addiction. We have conducted preliminary studies of cocaine withdrawal in rats using a variant of the forced swim test (FST), a method that may reflect symptoms of dysphoria. We administered cocaine (15 mg/kg, IP) or vehicle in a "binge" regimen (3 times per day at 1 hr intervals) for 2, 7, or 14 days. We then tested rats for immobility in the FST during cocaine withdrawal, at 1 or 3 days after the final injection. At 1 day withdrawal, rats treated previously with cocaine were more immobile in the FST than rats treated with vehicle. Surprisingly, the opposite effect was seen at 3 days cocaine withdrawal: rats previously treated with cocaine for 14 days were less immobile than those treated with vehicle. These preliminary data suggest that the FST is sensitive to behavioral adaptations that occur with repeated cocaine treatment, and may identify two distinct types of withdrawal symptoms: drug-opposite effects that accompany short-term (1 day) withdrawal, and drug-similar effects that accompany longer-term (3 days) withdrawal. We propose to further characterize these early findings. In Aim 1, we will determine if another cocaine dosing regimen, involving constant cocaine exposure, causes different withdrawal symptoms in the FST. In Aim 2, we will determine if the symptoms of cocaine withdrawal evident in the FST are also evident in a second behavioral assay, intracranial self-stimulation (ICSS). In Aim 3, we will determine if natural compounds that we have characterized in the FST (including cytidine, a citicoline metabolite) can attenuate the symptoms of cocaine withdrawal in this assay. In Aim 4, we will determine if the symptoms of cocaine withdrawal are associated with a molecular adaptation (increased function of CREB in the nucleus accumbens) previously associated with dysphoria. Together, these studies may facilitate the identification and development of innovative treatments that more effectively treat the symptoms of withdrawal from cocaine and other drugs of abuse.